Technical Abstract:
Vitamin E was originally discovered as a dietary factor essential for reproduction in rats. Since then, vitamin E has revealed many important molecular properties, such as the scavenging of reactive oxygen and nitrogen species, or the modulation of signal transduction and gene expression in antioxidant and non-antioxidant manners. A congenital disease, ataxia with vitamin E deficiency (AVED), characterized by impaired enrichment of alpha-tocopherol (aT) in plasma due to mutations in the alpha-tocopherol transfer protein gene, has been discovered. An effect of vitamin E on angiogenesis and vasculogenesis has been observed in several occasions, and recently it has been demonstrated in the placenta of pregnant ewes, possibly involving the stimulation of vascular endothelial growth factor (VEGF) expression by vitamin E. We recently observed that the phosphorylated form of alpha-tocopherol (aT), alpha-tocopheryl phosphate (aTP), increases the expression of VEGF. We propose that the stimulatory effect of aT on angiogenesis and vasculogenesis is potentiated by phosphorylation to aTP, which may act as a cofactor or active lipid mediator increasing VEGF expression. We hypothesize, that in a tissue undergoing rapid vasculogenesis such as the developing placenta, the VEGF level should be high, possibly as a consequence of increased activity of the aT kinase synthesizing the stimulating factor aTP. Therefore, we propose to assess whether the aT kinase activity and the aTP concentration are higher in placenta than in other tissues. If this hypothesis is proven correct, placenta could serve as a good source for purifying and cloning the aT kinase. Moreover, we would also assess whether aT or aTP can stimulate angiogenesis and vasculogenesis in an in vivo model, and characterize specific aTP receptors by which aTP up-regulates VEGF expression. Increased VEGF expression and consequent enhanced angiogenesis and vasculogenesis induced by aTP may explain not only the essential effects of vitamin E on reproduction, but also its beneficial effects against pre-eclampsia, ischemia/reperfusion injury, during wound healing and serve as a survival factor for brain and muscle cells. The finding that aTP may regulate placenta vasculogenesis may have as well important patho-physiological implications.